Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats

Abstract

Although estradiol (E 2 ) may have some beneficial effects as a treatment for menopause symptoms, E 2 also has trophic effects that can increase vulnerability to some cancers, such as breast cancer. In the present study, a model to investigate the concomitant behavioral and proliferative effects of E 2 was developed. First, the effects of different duration of chronic E 2 exposure (2 vs 6 months), or no such exposure, on proliferation (tumor incidence and weight, uterine weight) in adult, ovariectomized (OVX) rats was determined. Second, the effects of different dosages of E 2 (0.03 or 0.09 mg/kg) compared to vehicle only on sexual behavior, and measures of proliferation of adult OVX rats treated with a chemical carcinogen (DMBA; 1.25, 12.50, or 25.00 mg), or inert vehicle, were investigated. Vehicle or E 2 was administered subcutaneously (SC) to OVX rats once per week for 14 weeks. Six months of continuous E 2 exposure increased tumor incidence, tumor weight, and uterine weight, compared to 2 months of E 2 or no E 2 exposure. Rats administered DMBA had increased incidence, number, and size of tumors compared to vehicle treatment, and this effect appeared to be augmented by E 2 . Compared to vehicle, E 2 increased lordosis and uterine weight. Thus, E 2 may have the unfavorable effect of increasing proliferation when administered in chronic situations. Studies investigating the action of E 2 for these effects are ongoing.

Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats

“…These treatments were administered 44–48 hours before behavioral testing. E 2 dosing was based upon previous studies in our lab that have shown that this regimen produces physiological E 2 levels in plasma and brain at time of testing, decreases anxiety behavior, and increases lordosis of rats when they are tested 44–48 hours after injection (Frye et al, 1998; Walf & Frye, 2005; 2009ab). Raloxifene dosing was based upon pilot studies done in the lab in rats and mice, and the literature (Takahata et al, 2008; Walf and Frye, 2006).…”

“…As such, adult female rats, between 50 and 60 days of age, in the present study were administered a single dosing of an inert control substance (i.e. vegetable oil) or DMBA (Sigma; St. Louis, MO), as per described methods (Walf and Frye, 2009ab). …”

“…This dosing of DMBA was based upon dose-response studies of Huggins and our laboratory (Huggins, 1965; Walf and Frye, 2009ab). With higher dosing of DMBA (20 mg/kg) all rats survive carcinogen exposure, but there are shorter latencies to tumor growth and greater incidence of tumors, at this dosing than at lower dosages.…”

“…A similar pattern is observed in preclinical rodent models. For example, we have demonstrated that E 2 to female rats can have positive effects to reduce anxiety behaviors, but it can increase carcinogen-induced tumor incidence and uterine proliferation (Walf and Frye, 2009a,b). The source of positive and negative effects of estrogens in the central nervous system and peripheral tissues may be related to divergent mechanisms of action.…”

Estrogen action: A historic perspective on the implications of considering alternative approaches

“…Frye and Walf found that young adult, ovariectomized rats administered physiological dosages of subcutaneous E 2 had increased tumor incidence, which was potentiated with exposure to the chemical carcinogen, DMBA, which reliably induces mammary tumors [80,81]. In this model, E 2 increased uterine weight of rats, as well as had behavioral effects, irrespective of DMBA dosing [80,81]. Thus, E 2 can have trophic actions in ERα-associated tissues, and whole animal models may be used to further investigate the role and mechanisms of E 2 in these tissues as related to brain function, which is an ongoing question in this lab.…”